Nicotinamide Deficiency in Primary Open-Angle Glaucoma

Nzoughet, Judith Kouassi; Barca, Juan Manuel Chao de la; Guehlouz, Khadidja; Leruez, Stéphanie; Coulbault, Laurent; Allouche, Stéphane; Bocca, Cinzia; Muller, Jeanne; Amati‐Bonneau, Patrizia; Gohier, Philippe; Bonneau, Dominique; Simard, Gilles; Miléa, Dan; Lenaers, Guy; Procaccio, Vincent; Reynier, Pascal

doi:10.1167/iovs.19-27099

Cited by 83 publications

(59 citation statements)

References 26 publications

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“…However, in order to validate the nicotinamide deficiency, we previously measured the level of this vitamin using a targeted LC-MS/MS method specifically designed for the quantification of nicotinamide. The cohort of the current non-targeted study (34 POAG patients and 30 controls), as well as a replication cohort comprising 20 POAG patients and 15 controls were both analyzed [14]. Nicotinamide deficiency observed during the present non-targeted LC-HRMS metabolomics investigation was confirmed by targeted LC-MS/MS in both the initial cohort and the replication cohort, thus strengthening the results obtained in the present study.…”

Section: Discussionsupporting

confidence: 76%

“…In this respect, as detailed elsewhere [14], we proceeded to a blind independent external validation of nicotinamide, the metabolite identified by all four statistical Furthermore, in the context of biomarker discovery useful for clinical diagnosis, the selection of a restricted list of candidate markers is required before entering a subsequent qualification and verification phase [11][12][13]. In this respect, as detailed elsewhere [14], we proceeded to a blind independent external validation of nicotinamide, the metabolite identified by all four statistical approaches. Nicotinamide dosage using an independent quantitative method was performed on plasma samples from both the initial cohorts including 64 individuals reported in the current investigation, and replicative cohorts of 35 individuals.…”

Section: Resultsmentioning

confidence: 96%

“…Furthermore, in the context of biomarker discovery useful for clinical diagnosis, the selection of a restricted list of candidate markers is required before entering a subsequent qualification and verification phase [11][12][13]. In this respect, as detailed elsewhere [14], we proceeded to a blind independent external validation of nicotinamide, the metabolite identified by all four statistical Furthermore, in the context of biomarker discovery useful for clinical diagnosis, the selection of a restricted list of candidate markers is required before entering a subsequent qualification and verification phase [11][12][13]. In this respect, as detailed elsewhere [14], we proceeded to a blind independent external validation of nicotinamide, the metabolite identified by all four statistical approaches.…”

Section: Resultsmentioning

confidence: 99%

“…The study cohorts were composed of 34 POAG and 30 age-and sex-matched control individuals whose recruitment criteria and clinical features were recently described in a study focused on a quantitative dosage of nicotinamide [14]. Briefly, the individuals were recruited from the Department of Ophthalmology of Angers University Hospital, France.…”

Section: Study Cohortsmentioning

confidence: 99%

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A Data Mining Metabolomics Exploration of Glaucoma

et al. 2020

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Glaucoma is an age related disease characterized by the progressive loss of retinal ganglion cells, which are the neurons that transduce the visual information from the retina to the brain. It is the leading cause of irreversible blindness worldwide. To gain further insights into primary open-angle glaucoma (POAG) pathophysiology, we performed a non-targeted metabolomics analysis on the plasma from POAG patients (n = 34) and age- and sex-matched controls (n = 30). We investigated the differential signature of POAG plasma compared to controls, using liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS). A data mining strategy, combining a filtering method with threshold criterion, a wrapper method with iterative selection, and an embedded method with penalization constraint, was used. These strategies are most often used separately in metabolomics studies, with each of them having their own limitations. We opted for a synergistic approach as a mean to unravel the most relevant metabolomics signature. We identified a set of nine metabolites, namely: nicotinamide, hypoxanthine, xanthine, and 1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline with decreased concentrations and N-acetyl-L-Leucine, arginine, RAC-glycerol 1-myristate, 1-oleoyl-RAC-glycerol, cystathionine with increased concentrations in POAG; the modification of nicotinamide, N-acetyl-L-Leucine, and arginine concentrations being the most discriminant. Our findings open up therapeutic perspectives for the diagnosis and treatment of POAG.

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Section: Discussionsupporting

confidence: 76%

Section: Resultsmentioning

confidence: 96%

Section: Resultsmentioning

confidence: 99%

Section: Study Cohortsmentioning

confidence: 99%

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A Data Mining Metabolomics Exploration of Glaucoma

et al. 2020

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“…Nicotinamide deficiency and NAD depletion therefore have the potential to disrupt mitochondrial and energy metabolism and ganglion cell function. Recent work by Nzoughet et al 44 has demonstrated a significantly lower plasma nicotinamide concentration in POAG patients relative to controls which lends support to this hypothesis.…”

Section: Nicotinamide (Vitamin B3)mentioning

confidence: 74%

Neuroprotection in Glaucoma: Towards Clinical Trials and Precision Medicine

Khatib

Martin

2019

Current Eye Research

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Purpose: The eye is currently at the forefront of translational medicine and therapeutics. However, despite advances in technology, primary open-angle glaucoma remains the leading cause of irreversible blindness worldwide. Traditional intraocular pressure (IOP)-lowering therapies are often not sufficient to prevent progression to blindness, even in patients with access to high-quality healthcare. Neuroprotection strategies, which aim to boost the ability of target cells to withstand a pathological insult, have shown significant promise in animal models but none have shown clinically relevant efficacy in human clinical trials to date. We sought to evaluate the current status of neuroprotection clinical trials for glaucoma and identify limitations which have prevented translation of new glaucoma therapies to date. Methods: Literature searches identified English language references. Sources included MEDLINE, EMBASE, the Cochrane Library and Web of Science databases; reference lists of retrieved studies; and internet pages of relevant organisations, meetings and conference proceedings, and clinical trial registries. Results: We discuss six key neuroprotective strategies for glaucoma that have reached the clinical trial stage. Delivery of neurotrophic factors through gene therapy is also progressing towards glaucoma clinical trials. Refinements in trial design and the use of new modalities to define structural and functional endpoints may improve our assessment of disease activity and treatment efficacy. Advances in our understanding of compartmentalised glaucomatous degeneration and continued progress in the molecular profiling of glaucoma patients will enable us to predict individual risk and tailor treatment. Conclusion: New approaches to future glaucoma neuroprotection trials could improve the prospects for new glaucoma therapies. Glaucoma treatment tailored according to an individual's unique risk profile may become increasingly common in the future. ARTICLE HISTORY

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Nicotinamide and Pyruvate for Neuroenhancement in Open-Angle Glaucoma

et al. 2022

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IMPORTANCE Open-angle glaucoma may continue to progress despite significant lowering of intraocular pressure (IOP). Preclinical research has suggested that enhancing mitochondrial function and energy production may enhance retinal ganglion cell survival in animal models of glaucoma, but there is scant information on its effectiveness in a clinical setting.OBJECTIVE To test the hypothesis that a combination of nicotinamide and pyruvate can improve retinal ganglion cell function in human glaucoma as measured with standard automated perimetry.DESIGN, SETTING, AND PARTICIPANTS In this phase 2, randomized, double-blind, placebo-controlled clinical trial at a single academic institution, 197 patients were assessed for eligibility. Of these, 42 patients with treated open-angle glaucoma and moderate visual field loss in at least 1 eye were selected for inclusion and randomized. A total of 32 completed the study and were included in the final analysis. The mean (SD) age was 64.6 (9.8) years. Twenty-one participants (66%) were female. Participant race and ethnicity data were collected via self-report to ensure the distribution reflected that observed in clinical practice in the US but are not reported here to protect patient privacy. Recruitment took place in April 2019 and patients were monitored through December 2020. Data were analyzed from January to May 2021.INTERVENTIONS Ascending oral doses of nicotinamide (1000 to 3000 mg) and pyruvate (1500 to 3000 mg) vs placebo (2:1 randomization). MAIN OUTCOMES AND MEASURESNumber of visual field test locations improving beyond normal variability in the study eye. Secondary end points were the rates of change of visual field global indices (mean deviation [MD], pattern standard deviation [PSD], and visual field index [VFI]).RESULTS Twenty-two of 29 participants (76%) randomized to the intervention group and 12 of 13 participants (92%) randomized to placebo received their allocation, and 32 participants (32 eyes; ratio 21:11) completed the study (21 from the intervention group and 11 from the placebo group). Median (IQR) follow-up time was 2.2 (2.0-2.4) months. No serious adverse events were reported during the study. The number of improving test locations was significantly higher in the treatment group than in the placebo group (median [IQR], 15 [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] vs 7 [6-11]; P = .005). Rates of change of PSD suggested improvement with treatment compared with placebo (median, −0.06 vs 0.02 dB per week; 95% CI, 0.02 to 0.24; P = .02) but not MD (0.04 vs −0.002 dB per week; 95% CI, −0.27 to 0.09; P = .35) or VFI (0.09 vs −0.02% per week; 95% CI, −0.53 to 0.36; P = .71). CONCLUSIONS AND RELEVANCEA combination of nicotinamide and pyruvate yielded significant short-term improvement in visual function, supporting prior experimental research suggesting a role for these agents in neuroprotection for individuals with glaucoma and confirming the need for long-term studies to establish their usefulness in slowing progression.

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Nicotinamide Deficiency in Primary Open-Angle Glaucoma

Cited by 83 publications

References 26 publications

A Data Mining Metabolomics Exploration of Glaucoma

A Data Mining Metabolomics Exploration of Glaucoma

Neuroprotection in Glaucoma: Towards Clinical Trials and Precision Medicine

Nicotinamide and Pyruvate for Neuroenhancement in Open-Angle Glaucoma

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